{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T16:00:31Z","timestamp":1787673631844,"version":"build-2736575974"},"reference-count":51,"publisher":"Wiley","issue":"4-5","license":[{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004410","name":"European Molecular Biology Organization","doi-asserted-by":"publisher","award":["ALTF922\u20102022(SA)"],"award-info":[{"award-number":["ALTF922\u20102022(SA)"]}],"id":[{"id":"10.13039\/100004410","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000854","name":"Human Frontier Science Program","doi-asserted-by":"publisher","award":["LT0010\/2023\u2010L(SA)"],"award-info":[{"award-number":["LT0010\/2023\u2010L(SA)"]}],"id":[{"id":"10.13039\/501100000854","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011713","name":"Worldwide Cancer Research","doi-asserted-by":"publisher","award":["16\u20101153(GOF)"],"award-info":[{"award-number":["16\u20101153(GOF)"]}],"id":[{"id":"10.13039\/100011713","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/V009621\/1(A\u2010RP)"],"award-info":[{"award-number":["MR\/V009621\/1(A\u2010RP)"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C48390\/A21153(GOF)"],"award-info":[{"award-number":["C48390\/A21153(GOF)"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C7893\/A28990(A\u2010RPandYK)"],"award-info":[{"award-number":["C7893\/A28990(A\u2010RPandYK)"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["CTRQQR\u20102021\\100004(JC,JF,JKandJS)"],"award-info":[{"award-number":["CTRQQR\u20102021\\100004(JC,JF,JKandJS)"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["DRCNPG\u2010May21|100004(BCICorefacilities)"],"award-info":[{"award-number":["DRCNPG\u2010May21|100004(BCICorefacilities)"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT203148\/Z\/16\/Z(GOF)"],"award-info":[{"award-number":["WT203148\/Z\/16\/Z(GOF)"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Lung cancer is the leading cause of cancer\u2010related death globally. To better understand the biology of lung cancer, mouse models have been developed using either tail vein\u2010injected tumour cell lines or genetically modified mice. The current gold\u2010standard models typically present with multiple lung foci. However, although these models are widely used, their correlation with human disease are limited, as early\u2010stage human lung cancer usually presents as a single lesion rather than multiple foci. Additionally, a major challenge of using multifocal lung tumour models is the difficulty in distinguishing primary lung tumours from intrathoracic metastasis and lethal levels of lung congestion before distant metastases develop. Here, we present a refined and detailed surgical method in which murine tumour cells [Lewis lung carcinoma (LLC), alveogenic lung carcinoma (CMT), or <jats:italic>Kras\/Trp53\u2010<\/jats:italic>KP mutant cells] were injected directly into the left lung lobe of C57BL\/6 mice, or, alternatively, adenoviral\u2010Cre or adenoviral\u2010FlpO was administered directly into the left lung lobe of <jats:italic>Kras<\/jats:italic><jats:sup><jats:italic>LSL\u2010G12D<\/jats:italic><\/jats:sup>;<jats:italic>Trp53<\/jats:italic><jats:sup><jats:italic>fl\/fl<\/jats:italic><\/jats:sup> or <jats:italic>Kras<\/jats:italic><jats:sup><jats:italic>FSF\u2010G12D<\/jats:italic><\/jats:sup>;<jats:italic>Trp53<\/jats:italic><jats:sup><jats:italic>frt\/frt<\/jats:italic><\/jats:sup> (KP) mice, respectively. This method generated unifocal primary left lung lobe tumours with traceable spread to local and distant sites. A cross\u2010comparison of the unifocal models described commonalties and differences between LLC, CMT, KP cells, and adenoviral\u2010Cre or \u2010FlpO methods in terms of timings for primary lung tumour growth and traceable spread to local and distant sites, histological analysis of CD3 and CD11b immune cell infiltration, and Picrosirius Red analysis of extracellular matrix complexity. Lastly, the frequency of clinical histopathological features typical of human lung cancer were assessed across the unifocal mouse models to provide a direct comparison with human lung cancer. Overall, this study details a refined and reproducible protocol for intralobular lung injection to generate unifocal lung cancer models that resemble key features of human lung cancer. This approach can be applied to other lung cancer initiation strategies. The cross\u2010comparative histological analysis across the models tested here offers a valuable resource to aid researchers in selecting the most appropriate next\u2010generation unifocal lung cancer models for their specific research needs. \u00a9 2025 The Author(s). <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6435","type":"journal-article","created":{"date-parts":[[2025,6,29]],"date-time":"2025-06-29T10:17:02Z","timestamp":1751192222000},"page":"405-420","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Development and characterisation of improved unifocal primary mouse lung cancer models with metastatic potential"],"prefix":"10.1002","volume":"266","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4421-6968","authenticated-orcid":false,"given":"Ana\u2010Rita","family":"Pedrosa","sequence":"first","affiliation":[{"name":"Adhesion and Angiogenesis Lab, Centre for Tumour Microenvironment, John Vane Science Centre, Barts Cancer Institute Queen Mary University  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Castillo\u2010Kauil","sequence":"additional","affiliation":[{"name":"Adhesion and Angiogenesis Lab, Centre for Tumour Microenvironment, John Vane Science Centre, Barts Cancer Institute Queen Mary University  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuliia","family":"Kravchuk","sequence":"additional","affiliation":[{"name":"Adhesion and Angiogenesis Lab, Centre for Tumour Microenvironment, John Vane Science Centre, Barts Cancer Institute Queen Mary University  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Adhesion and Angiogenesis Lab, Centre for Tumour Microenvironment, John Vane Science Centre, Barts Cancer Institute Queen Mary University  London UK"},{"name":"Department of Pathology University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Williams","sequence":"additional","affiliation":[{"name":"Adhesion and Angiogenesis Lab, Centre for Tumour Microenvironment, John Vane Science Centre, Barts Cancer Institute Queen Mary University  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Moore","sequence":"additional","affiliation":[{"name":"Department of Pathology CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron","family":"Lang","sequence":"additional","affiliation":[{"name":"Imaging Therapies and Cancer, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srinivas","family":"Allanki","sequence":"additional","affiliation":[{"name":"Tumour Cell Biology Lab The Francis Crick Institute  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Maniati","sequence":"additional","affiliation":[{"name":"Centre for Cancer Evolution, John Vane Science Centre, Barts Cancer Institute Queen Mary University  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9906-7552","authenticated-orcid":false,"given":"Alexandros","family":"Hardas","sequence":"additional","affiliation":[{"name":"Royal Veterinary College  Hertfordshire UK"},{"name":"Francis Crick Institute  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jozafina","family":"Haj","sequence":"additional","affiliation":[{"name":"Adhesion and Angiogenesis Lab, Centre for Tumour Microenvironment, John Vane Science Centre, Barts Cancer Institute Queen Mary University  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Drake","sequence":"additional","affiliation":[{"name":"Adhesion and Angiogenesis Lab, Centre for Tumour Microenvironment, John Vane Science Centre, Barts Cancer Institute Queen Mary University  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Cleaver","sequence":"additional","affiliation":[{"name":"Cancer Imaging Lab, Centre for Cancer Biomarkers and Biotherapeutics, John Vane Science Centre, Barts Cancer Institute Queen Mary University  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Foster","sequence":"additional","affiliation":[{"name":"Cancer Imaging Lab, Centre for Cancer Biomarkers and Biotherapeutics, John Vane Science Centre, Barts Cancer Institute Queen Mary University  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Kim","sequence":"additional","affiliation":[{"name":"Cancer Imaging Lab, Centre for Cancer Biomarkers and Biotherapeutics, John Vane Science Centre, Barts Cancer Institute Queen Mary University  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ester","family":"Stern","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Hadassah Medical Center and Faculty of Medicine Hebrew University  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Sosabowski","sequence":"additional","affiliation":[{"name":"Cancer Imaging Lab, Centre for Cancer Biomarkers and Biotherapeutics, John Vane Science Centre, Barts Cancer Institute Queen Mary University  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilbert O.","family":"Fruhwirth","sequence":"additional","affiliation":[{"name":"Imaging Therapies and Cancer, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Sahai","sequence":"additional","affiliation":[{"name":"Tumour Cell Biology Lab The Francis Crick Institute  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ori","family":"Wald","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Hadassah Medical Center and Faculty of Medicine Hebrew University  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kairbaan","family":"Hodivala\u2010Dilke","sequence":"additional","affiliation":[{"name":"Adhesion and Angiogenesis Lab, Centre for Tumour Microenvironment, John Vane Science Centre, Barts Cancer Institute Queen Mary University  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,18]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-4975(96)00220-2"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-020-00881-7"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2021.08.1994"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/621324"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsob.200247"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-2193"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.30.8304"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-2297-0_5"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00124709"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1284505"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-023-03542-z"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6690178"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471141755.ph1427s62"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-01044-4"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-021-01442-6"},{"key":"e_1_2_9_17_1","article-title":"Radionuclide\u2010fluorescence reporter gene imaging to track tumor progression in rodent tumor models","volume":"13","author":"Volpe A","year":"2018","journal-title":"J Vis Exp"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.113.127480"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.95"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.2174\/156652312799789235"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2012-1036"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-22-0325"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-16-0365"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1177\/17588359211006950"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0179-8"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202000880"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.athoracsur.2010.12.028"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.21037\/jtd-21-1597"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000000409"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1097\/JTO.0000000000000486"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-020-00709-2"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2022.07.016"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2018.02.108"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2010.141861"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1097\/JTO.0000000000000630"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmcr.2020.101225"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001764"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.neo.7900098"},{"key":"e_1_2_9_39_1","first-page":"5532","article-title":"Development of an orthotopic model to study the biology and therapy of primary human lung cancer in nude mice","volume":"9","author":"Onn A","year":"2003","journal-title":"Clin Cancer Res"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6870"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05783-5"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05706-4"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05874-3"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.009084"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1534\/g3.117.300327"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-230X(08)60970-7"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13898"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2015.09.009"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2022.01.007"},{"key":"e_1_2_9_50_1","article-title":"Applying stereotactic injection technique to study genetic effects on animal behaviors","author":"McSweeney C","year":"2015","journal-title":"J Vis Exp"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1097\/JTO.0000000000000367"},{"key":"e_1_2_9_52_1","doi-asserted-by":"crossref","unstructured":"CarolineM SauerMDE ViasM et al.Absolute copy number fitting from shallow whole genome sequencing data bioRxiv2021; 452658v1. [Not peer reviewed].","DOI":"10.1101\/2021.07.19.452658"}],"updated-by":[{"DOI":"10.1002\/path.6489","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T00:00:00Z","timestamp":1760227200000}}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.6435","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T10:26:06Z","timestamp":1761042366000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.6435"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,18]]},"references-count":51,"journal-issue":{"issue":"4-5","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1002\/path.6435"],"URL":"https:\/\/doi.org\/10.1002\/path.6435","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,18]]},"assertion":[{"value":"2024-05-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}